PROJECT SUMMARY/ABSTRACT Rett syndrome is a devastating childhood neurological disorder that robs young girls of their motor, language, and social skills. Although the genetic cause of Rett syndrome was discovered two decades ago, the precise mechanism by which mutations in MECP2 cause Rett syndrome has remained elusive. Such a critical gap in knowledge has hindered the development of effective treatments. Previous studies have highlighted the importance of MeCP2 in many brain regions. However, the role of MeCP2 in orchestrating the functions of the cerebellum remains unknown, despite motor incoordination and ataxia being prominent features in Rett syndrome. To address this, I studied mice conditionally lacking Mecp2 in the cerebellum and found that they displayed motor defects that improved with extended training. I used neuroanatomical analysis, in vivo calcium imaging, and in vivo electrophysiology to explore the underlying network dysfunction in the cerebellum. The fact that extended training rescued the motor defects raised the exciting possibility that neural circuits affected by MeCP2 dysfunction are amenable to intervention. I validated this hypothesis by demonstrating that extended training in symptomatic Mecp2+/- female (Rett) mice, a clinically relevant model of global MeCP2 dysfunction, partially ameliorated their motor impairments. Because the clinical course of Rett syndrome starts with a period of normal development, I performed motor training beginning in the pre-symptomatic period. To my surprise, pre-symptomatic training dramatically improved the motor performance of Rett mice. I will build on these encouraging results and explore the ability of extended training to overcome defects in spatial learning, another debilitating feature of Rett syndrome. These discoveries will provide mechanistic insights into the origin of the motor incoordination and ataxia that plagues patients with Rett syndrome, and raise the exciting possibility that extended training might improve multiple symptoms of the disease. The implications of this study have therapeutic potential as pre-symptomatic diagnosis and early rehabilitation may be the key to modifying clinical aspects of Rett syndrome.